The aim of this proposal is to elucidate the mechanisms underlying the exaggerated startle response which is one of the hallmarks of Post Traumatic Stress Disorder (PTSD). Animal studies of inescapable shock and psychophysiological investigations in Vietnam war veterans with PTSD suggest that both conditioned and unconditioned mechanisms must be considered in the pathogenesis of PTSD. The conceptual framework for the proposed study is based on animal models of conditioned and unconditioned stress-induced startle modulation, namely, fear- potentiated startle, shock sensitization of startle, and stress-induced loss of prepulse inhibition. Hyperreactivity of PTSD veterans may also point to a general deficit in processing environmental stimuli. We have found that PTSD veterans engaged excessive attention toward external stimuli. We will attempt to further characterize this deficit using event-related potentials (ERP). We will also conduct a study using brainstem auditory evoked potentials (BAEP) to explore sensory processing. The relationship between any impairments in information processing and abnormal startle modulation will also be examined. Startle modulation and processing of external stimuli will be investigated both at baseline and during experimentally-induced stress in veterans with PTSD (N=44) and appropriate civilian (N=82) and veteran (N=81) control subjects. The stress conditions will consist of anticipation of electric shocks and the viewing of traumatic scenes. The eyeblink component of the startle reflex elicited by an intense acoustic stimulus with abrupt onset will be measured electromyographically. Cognitive processing of external stimuli will be investigated with ERPs elicited by various types of stimuli that are designed to attract the subject's attention. The BAEPs will be measured at baseline only. The results of the proposed study will clarify whether the increased reactivity to sensory stimulation in PTSD reflects a chronic elevated arousal or a stimulus-induced state. These experiments may provide a foundation for more objective diagnostic approaches and a better assessment of treatment outcome through the characterization of core symptoms of PTSD. In addition, our current state of knowledge from the delineation of the neurobiological substrates of stress-related startle modulation in animals could lead to the identification of patterns of brain dysregulation involved in PTSD and could ultimately result in the development of better behavioral and pharmacological treatment approaches for this disorder.